Abstract: Lysosomes are essential focal points of cellular metabolism, digesting a wide range of macromolecules provided by endocytosis or autophagy. To this end, lysosomes rely on their highly acidic luminal pH to promote the function of their many enzymes, a pH generated by the action of a v-Type proton pumping ATPase. Since this transporter is electrogenic, parallel ion movements must occur to dissipate the generated membrane potential and promote bulk proton flux. I will present evidence that the Cl-/H+ antiporter, ClC-7, plays this role, moving Cl- to dissipate the lysosomal transmembrane voltage. However, the function of ClC-7 has been controversial, with conflicting reports on its contribution to lysosomal acidification. All heretofore known patients with ClC-7 functional mutations have varying degrees of the same disease, with osteopetrosis sometimes associated with lysosomal storage disease. Here, we report on two patients with a novel disease manifested as widespread lysosomal dysfunction but no bone abnormalities, who both have the same missense mutation in ClC-7. We find that fibroblasts from both patients have acidification abnormalities and that heterologously expressed human ClC-7 carrying this mutation displays a novel phenotype under electrophysiological measurements. These findings provide strong support for an important role of ClC-7 in the lysosomal acidification process and suggest opportunities for therapies for these patients.